Current Issue : July - September Volume : 2015 Issue Number : 3 Articles : 5 Articles
Background: Acute lung injury (ALI) and its most severe form acute respiratory distress syndrome (ARDS) have\nbeen the leading cause of morbidity and mortality in intensive care units (ICU). Currently, there is no effective\npharmacological treatment for acute lung injury. Curcumin, extracted from turmeric, exhibits broad anti-inflammatory\nproperties through down-regulating inflammatory cytokines. However, the instability of curcumin limits its clinical\napplication.\nMethods: A series of new curcumin analogs were synthesized and screened for their inhibitory effects on the\nproduction of TNF-? and IL-6 in mouse peritoneal macrophages by ELISA. The evaluation of stability and mechanism of\nactive compounds was determined using UV-assay and Western Blot, respectively. In vivo, SD rats were pretreatment\nwith c26 for seven days and then intratracheally injected with LPS to induce ALI. Pulmonary edema, protein\nconcentration in BALF, injury of lung tissue, inflammatory cytokines in serum and BALF, inflammatory cell\ninfiltration, inflammatory cytokines mRNA expression, and MAPKs phosphorylation were analyzed. We also\nmeasured the inflammatory gene expression in human pulmonary epithelial cells.\nResults: In the study, we synthesized 30 curcumin analogs. The bioscreeening assay showed that most compounds\ninhibited LPS-induced production of TNF-? and IL-6. The active compounds, a17, a18, c9 and c26, exhibited their\nanti-inflammatory activity in a dose-dependent manner and exhibited greater stability than curcumin in vitro.\nFurthermore, the active compound c26 dose-dependently inhibited ERK phosphorylation. In vivo, LPS significantly\nincreased protein concentration and number of inflammatory cells in BALF, pulmonary edema, pathological\nchanges of lung tissue, inflammatory cytokines in serum and BALF, macrophage infiltration, inflammatory gene\nexpression, and MAPKs phosphorylation. However, pretreatment with c26 attenuated the LPS induced increase\nthrough ERK pathway in vivo. Meanwhile, compound c26 reduced the LPS-induced inflammatory gene expression\nin human pulmonary epithelial cells.\nConclusions: These results suggest that the novel curcumin analog c26 has remarkable protective effects on\nLPS-induced ALI in rat. These effects may be related to its ability to suppress production of inflammatory cytokines\nthrough ERK pathway. Compound c26, with improved chemical stability and bioactivity, may have the potential to be\nfurther developed into an anti-inflammatory candidate for the prevention and treatment of ALI....
Background: Fibrotic remodeling of airway and lung parenchymal compartments is attributed to pulmonary\ndysfunction with an involvement of reactive oxygen species (ROS) in chronic lung diseases such as idiopathic\npulmonary fibrosis and asthma.\nMethods: The in vitro study elucidated inhibitory effects of astragalin, kaempferol-3-O-glucoside from leaves of\npersimmon and green tea seeds, on oxidative stress-induced airway fibrosis. The in vivo study explored the demoting\neffects of astragalin on epithelial to mesenchymal transition in BALB/c mice sensitized with ovalbumin (OVA).\nResults: The exposure of 20 ?M H2O2 for 72 h accelerated E-cadherin loss and vimentin induction in airway epithelial\nBEAS-2B cells, which was reversed by non-toxic astragalin at 1ââ?¬â??20 ?M. Astragalin allayed the airway tissue levels of ROS\nand vimentin enhanced by OVA challenge. Collagen type 1 production increased in H2O2ââ?¬â??exposed epithelial cells and\ncollagen fiber deposition was observed in OVA-challenged mouse airways. This study further investigated that\nthe oxidative stress-triggered autophagic regulation was responsible for inducing airway fibrosis. H2O2 highly\nenhanced the expression induction of the autophagy-related beclin-1 and light chains 3A/B (LC3A/B) within 4 h\nand astragalin blocked such induction by H2O2. This compound deterred the ROS-promoted autophagosome\nformation in BEAS-2B cells. Consistently, in OVA-sensitized mice the expression of beclin-1 and LC3A/B was\nhighly induced, and oral administration of astragalin suppressed the autophagosome formation with inhibiting\nthe induction of these proteins in OVA-challenged airway subepithelium. Induction of autophagy by spermidine\ninfluenced the epithelial induction of E-cadherin and vimentin that was blocked by treating astragalin.\nConclusion: These results demonstrate that astragalin can be effective in allaying ROS-promoted bronchial\nfibrosis through inhibiting autophagosome formation in airways....
Background: Inhaled corticosteroid/long-acting ?2-agonist combinations (ICS/LABA) have emerged as first line\ntherapies for chronic obstructive pulmonary disease (COPD) patients with exacerbation history. No randomized clinical\ntrial has compared exacerbation rates among COPD patients receiving budesonide/formoterol combination (BFC) and\nfluticasone/salmeterol combination (FSC) to date, and only limited comparative data are available. This study compared\nthe real-world effectiveness of approved BFC and FSC treatments among matched cohorts of COPD patients in a large\nUS managed care setting.\nMethods: COPD patients (?40 years) naive to ICS/LABA who initiated BFC or FSC treatments between 03/01/2009-03/31/2012\nwere identified in a geographically diverse US managed care database and followed for 12 months; index date\nwas defined as first prescription fill date. Patients with a cancer diagnosis or chronic (?180 days) oral corticosteroid (OCS)\nuse within 12 months prior to index were excluded. Patients were matched 1-to-1 on demographic and pre-initiation\nclinical characteristics using propensity scores from a random forest model. The primary efficacy outcome was COPD\nexacerbation rate, and secondary efficacy outcomes included exacerbation rates by event type and healthcare resource\nutilization. Pneumonia objectives included rates of any diagnosis of pneumonia and pneumonia-related healthcare\nresource utilization.\nResults: Matching of the identified 3,788 BFC and 6,439 FSC patients resulted in 3,697 patients in each group. Matched\npatients were well balanced on age (mean = 64 years), gender (BFC: 52% female; FSC: 54%), prior COPD-related medication\nuse, healthcare utilization, and comorbid conditions. During follow-up, no significant difference was seen between BFC and\nFSC patients for number of COPD-related exacerbations overall (rate ratio [RR] = 1.02, 95% CI = [0.96,1.09], p = 0.56) or by\nevent type: COPD-related hospitalizations (RR = 0.96), COPD-related ED visits (RR = 1.11), and COPD-related office/outpatient\nvisits with OCS and/or antibiotic use (RR = 1.01). The proportion of patients diagnosed with pneumonia during the\npost-index period was similar for patients in each group (BFC = 17.3%, FSC = 19.0%, odds ratio = 0.92 [0.81,1.04],\np = 0.19), and no difference was detected for pneumonia-related healthcare utilization by place of service....
Murine models for the study of lung cancer have historically been the backbone of preliminary preclinical data to support early\nhuman clinical trials. However, the availability of multiple experimental systems leads to debate concerning which model, if any,\nis best suited for a particular therapeutic strategy. It is imperative that these models accurately predict clinical benefit of therapy.\nThis review provides an overview of the current murine models used to study lung cancer and the advantages and limitations of\neach model, as well as a retrospective evaluation of the uses of each model with respect to accuracy in predicting clinical benefit of\ntherapy. A better understanding of murine models and their uses, as well as their limitations may aid future research concerning\nthe development and implementation of new targeted therapies and chemotherapeutic agents for lung cancer....
Purpose YKL-40 is a chitinase-like protein found to\ncorrelate with asthma as well as numerous infectious and\nautoimmune diseases or cancer. The aim of the present\nstudy was to investigate the role of YKL-40 as a possible\nmarker of asthma and its associations with factors differentiating\nphenotypes of asthma.\nMethods The study group comprised 167 patients, including\n116 women and 51 men aged 18ââ?¬â??88 years with\nchronic asthma. The control group comprised 81 healthy\nindividuals, including 50 women and 31 men aged\n19ââ?¬â??86 years. In every participant, medical history was\ntaken; spirometry and skin prick tests were performed.\nYKL-40 was determined in sera by means of ELISA test.\nResults Mean serum YKL-40 level was 59.7 ng/ml\n(53.6ââ?¬â??65.7 ng/ml; 95 %CI) with significant difference between\nasthmatics and healthy controls (mean values: 66.8 Ã?± 53.8 vs.\n44.9 Ã?± 29.4 ng/ml; p\\0.001). In asthmatics, the level was\nsignificantly higher in subgroup with poor control of symptoms\nand exacerbations (91.8 Ã?± 57.1 ng/ml) compared to stable\nasthmatics (59.6 Ã?± 50.8 ng/ml; p\\0.001) as well as in atopic\ncompared to non-atopic asthmatics (77.2 Ã?± 53.9 vs.\n61.1 Ã?± 57.8 ng/ml; p\\0.001). Mean YKL-40 level in obese\nasthmatics was 135.6 ng/ml compared to 50.0 ng/ml in nonobese\n(p\\0.001).Whenphenotypes of early-onset atopic, lateonset\nnon-atopic, and obesity-related asthma were compared,\nYKL-40 levels were 80.62 Ã?± 46.9, 51.5 Ã?± 24.9, and\n168.1 Ã?± 71.5 ng/ml, respectively (p\\0.05).\nConclusion Although YKL-40 is not a specific marker for\nasthma, it correlates with some clinical features such as\nexacerbation, level of control, atopy, and obesity....
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